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Merck

Impairment of Proteasome Function in Podocytes Leads to CKD.

Journal of the American Society of Nephrology : JASN (2021-01-30)
Shin-Ichi Makino, Naritoshi Shirata, Juan Alejandro Oliva Trejo, Kanae Yamamoto-Nonaka, Hiroyuki Yamada, Takafumi Miyake, Kiyoshi Mori, Takahiko Nakagawa, Yoshitaka Tashiro, Hirofumi Yamashita, Motoko Yanagita, Ryosuke Takahashi, Katsuhiko Asanuma
摘要

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood. To investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 (Rpt3 pdKO), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function. Rpt3 pdKO mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt3pdKO mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3 pdKO mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3 pdKO mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3 pdKO mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes. Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.

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Sigma-Aldrich
抗-GAPDH抗体,小鼠单克隆 小鼠抗, clone GAPDH-71.1, purified from hybridoma cell culture
Sigma-Aldrich
蛋白酶体 20S 活性检测试剂盒, sufficient for 100 fluorometric tests